Perturbations in sodium homeostasis are, unarguably, a central pathophysiologic lesion in heart failure (HF). Unfortunately, attempts to prevent or treat volume overload with salt restriction can further worsen the sodium avid state. Recent literature, spanning experimental to epidemiologic, has highlighted the double edged sword of salt restriction, finding that neurohormonal activation, volume status and even outcomes can sometimes improve with higher salt intake. While it is clear that sodium drives volume overload, a significant body of literature has confirmed renal salt sensing relies on chloride rather than sodium. It has been known for decades that renal responses such as tubuloglomerular feedback and renin release are governed by chloride. Recently, a family of serine-threonine kinases (With-No-Lysine (K), WNK) have been identified as the molecular sensor for chloride and master regulator of sodium transporters in the kidney. The above observations led us to hypothesize that chloride may be an important target in HF and over a series of 7 manuscripts we have demonstrated that chloride, rather than sodium, is primarily associated with diuretic resistance, neurohormonal activation and mortality in HF. Moreover, in a pilot study we demonstrated that administration of three days of 115 mmol/day of sodium-free chloride (as lysine chloride) caused a substantial downregulation in renal sodium transporters and multiple signals supporting improvement in volume status. The overarching goal of the current proposal is to address the fundamental gaps in our understanding of chloride homeostasis in HF, facilitating the translation of a large body of promising experimental and observational literature into a potentially viable therapeutic approach in HF. To achieve this goal, we propose a classic and rigorous placebo controlled crossover inpatient ?GCRC? balance study (n=20 participants), a placebo controlled ?real world? efficacy study in decompensated HF patients receiving aggressive IV diuretics (n=100 patients) and innovative interrogation of renal structural (quantitation of renal tubular solute transporters using urinary exosomes) and functional changes (using lithium clearance, the ?gold standard? technique to query in vivo proximal tubular sodium handling). Our aims are to 1) To understand the quantitative effects of sodium free chloride supplementation on electrolyte balance, volume status, and sodium avidity in stable HF patients in a highly controlled inpatient environment. 2) To determine if sodium free chloride supplementation will improve volume status in the real world setting of decompensated HF treated with aggressive use of IV loop diuretics. 3) To determine if sodium free chloride supplementation induces an intra-renal pattern of change consistent with suppression of WNK including deactivation of downstream kinases, reduction of the quantity of WNK regulated sodium cotransporters, and a redistribution of intra-renal sodium reabsorption.